Colorectal cancer (CRC) remains the second most common cause of cancer mortality worldwide, and among Veterans in the United States, the third despite the successful implementation of successful preventive screening measures. One contributing factor that has newly emerged is the rapid development of cancers in small, sessile adenomas (polyps), with mutational processes and signatures that drive early CRC tumorigenesis. Yet, to date, biomarkers and risk factors for polyps (adenomas) that inordinately and rapidly develop into colon cancer remain poorly defined. We recently observed surprisingly high mutational profiles through whole-genome sequence (WGS) analysis in 2 of 4 pairs of benign colorectal adenoma tissue samples. Extending this to unsupervised hierarchical clustered transcriptomic analysis of a further 7 pairs of adenomas reveals distinct mutational signatures regardless of adenoma size. Strikingly, we observe mutations in the TGF-? pathway and CEA-associated genes in 4 out of 11 adenomas, overlapping with the Wnt pathway. Immunohistochemical labeling reveals a nearly 5-fold increase in CEA levels in 23% of adenoma samples tested, with a concomitant loss of TGF-? signaling. We have defined a functional role by which the CEA B3 domain interacts with TGFBR1, potentially inactivating the tumor suppressor function of TGF-? signaling. Raised CEA levels occur with concomitant loss of TGF-? signaling and activation of oncogenic molecules that include STAT3. Furthermore, deletion of Smad3/4 adaptor ?2SP results in loss of TGF-? signaling, with a spontaneous formation of adenomas as well as overt CRC, and presents a strong mouse model of CRC. The overall hypothesis of this application is that disruption of the TGF-? tumor suppressor pathway, and concomitantly raised levels of oncogenic molecules such as CEA, STAT3, disrupt normal colonic mucosa and promote oncogenesis in CRC. Our aims are to: AIM 1a) Expand and validate the significance of loss of the TGF-? pathway associated with high CEA and/or CEACAM6 levels as prognostic factors in advanced adenomas that rapidly progress to CRC through i) First, whole transcriptomic sequence, immunohistochemical and RT-PCR analyses of 40 additional adenomas ii) Secondly, by examining The Cancer Genome Atlas (TCGA) Pan gastrointestinal cancer (GI) datasets to obtain a complete evaluation of our findings. 1b) Determine whether CEA/CEACAM6 and STAT3 with loss of TGF-? signaling are drivers of early CRC in vivo. 2 a) Determine the molecular mechanisms by which CEA inhibits the TGF-? tumor suppressor pathway in early and advanced CRC. We plan to accomplish this through i) Analyzing the role of CEA and CEACAM6 in the disruption of the TGF-? pathway and concomitant IL-6/STAT3 activation in CRC. ii) Determine antitumor activity of CEA inhibition, with and without STAT3 inhibitors and characterize their mechanisms of action. Through translational studies- interrogating human cell lines/genomics, and animal model systems of colon cancer, this application proposes an integrated approach for human CRC, providing novel insights into early and advanced CRC. With vaccines available, as well as new low toxicity therapeutics, identifying specific populations particularly among Veterans with multiple co-morbidities, that could respond to treatment, these goals are centrally important for improving the quality of life under treatment, as well as the mortality from this common cancer.